Many disease conditions are characterized by differences in levels of gene expression in the presence or concentration of specific proteins and other biomarkers. Within this context, there is the possibility of using predictive models (methods) to aid disease diagnosis.
Meningitis is the inflammation of the meninges in response to infection or exposure to chemical agents. According to the etiology, meningitis are classified as aseptic (AM), with no evidence of causative bacterial infection, or bacterial (BM). While AMs, are mostly are benign and of self-limited course, BMs are associated with high mortality and morbidity that have remained unchanged in the last decades despite the advances in antimicrobial therapy and intensive care aimed at maintaining patients' vital systems (Scheld W, Koedel U, Nathan B, Pfister H: Pathophysiology of bacterial meningitis: mechanism(s) of neuronal injury. J Infect Dis 2002, 186 Suppl 2:S225-233).
Bacterial meningitis (BM) is one of the top ten causes of death related to infections worldwide (Fauci A. Infectious diseases: considerations for the 21st century, Clin Infect Dis 2001, 32(5):675-685), with an estimated incidence of 2 5/100 thousand cases per year in developed countries, reaching values up to ten times higher in developing countries (Murray J, Lopez A: Global burden of disease and injuries series. Geneva; 1996.). MB is associated with a mortality rate up to 30%. Furthermore, from 30 to 50% of patients who survive the infection develop permanent neurological sequelae, including sensorineural deafness, intellectual disability, learning disabilities, sensory and physical disabilities and cerebral palsy (Merkelbach S, Sittinger H, Schweizer I, Muller M: Cognitive outcome after bacterial meningitis. Acta Neurol Scand 2000, 102(2):118-123).
The most common etiologic agents of MB are Streptococcus pneumoniae (pneumococci), Neisseria meningitidis (meningococci), and type B Haemophilus influenzae (Hib). Since the creation and inclusion of anti-Hib vaccine in the basic vaccination schedule, at the end of the 90s, pneumococci have become the most frequent causative agent of non-epidemic MB acquired in the community among children over one year old (Schuchat A, Robinson K, Wenger J, Harrison L, Farley M, Reingold A, Lefkowitz L, Perkins B. Bacterial meningitis in the United States in 1995. Active Surveillance Team. N Engl J Med 1997, 337(14):970-976). Among BMs, pneumococcal meningitis is the one associated with the highest mortality and morbidity rates. Meningococcal meningitis is mainly an epidemic disease and affects mainly children and young adults.
Aseptic meningitis (AM) is defined as an inflammation of the subarachnoid space, characterized by mononuclear cells pleocytosis and by sterile CSF (cerebrospinal fluid or cerebrospinal fluid) culture. Although the primary cause of AMs are viral infections, AM differential diagnosis includes also tuberculous or fungal meningitis, inflammation caused by parameningeal infection, collagen vascular diseases and meningeal inflammations caused by drug (Ravel R: Clinical Laboratory Medicine: Clinical Application of Laboratory Data: Elsevier Health Sciences; 1994). Viral meningitis are common and often not reported. Non-poliovirus enteroviruses (Coxsackievirus and Echovirus) are responsible for 80 to 90% of the cases of viral meningitis with determined etiology (Atkinson P, Sharland M, Maguire H: Predominant enteroviral serotypes causing meningitis. Archives of Disease in Childhood 1998, 78:373-374).
BMs are characterized by an intense granulocytic inflammation in the subarachnoid and ventricular spaces, which extends to the perilymphatic space of the inner ear and causes neuronal death, mainly in the cerebral cortex (CX) and hippocampus (HC) and in the cochlear spiral ganglion. In pneumococcal meningitis, cortical areas with morphologic evidence of acute neural necrosis are observed, apoptosis being the predominant form of neuronal damage in the HC (Meli D, Christen S, Leib S, Tauber M: Current concepts in the pathogenesis of meningitis caused by Streptococcus pneumoniae. Curr Opin Infect Dis 2002, 15(3):253-257). The inflammatory response to infection determines the BM clinical result. The cascade of inflammatory evens that drives BM pathogenesis is initiated by the presence of the bacteria in the CSF. Bacterial components stimulate the production and release by endothelial cells, astrocytes and microglia, of inflammatory mediators that can directly injure the brain tissue, interact with other modulators of the inflammatory response, or also induce secondary mechanisms capable of causing brain damage (Koedel U, Pfister H: Oxidative stress in bacterial meningitis. Brain Pathol 1999, 9(1):57-67). Another remarkable characteristic of BM is the increased permeability of the blood-brain barrier, which affects homeostasis in the neuronal microenvironment.
Most data on the pathophysiology of MB were obtained from studies using experimental models of pneumococcal meningitis. Little is known about the pathophysiology of meningococcal meningitis. If, on one hand, it is reasonable to formulate some extrapolations from the results of studies focused on the pneumococcal disease, the differences in mortality and morbidity rates between pneumococcal meningitis and meningococcal have remained unexplained.
The inflammatory process observed in patients affected by enterovirus AM is much less well-known than in the case of BM. It is known that the inflammatory response is triggered by the penetration of the virus in the central nervous system (CNS), mainly by hematogenic dissemination from primary infections sites (Tunkel A, Wispelwey B, Scheld W: Pathogenesis and pathophysiology of meningitis. Infect Dis Clin North Am 1990, 4(4):555-581). The presence of the virus in the CNS induces the production/release of proinflammatory cytokines that promote infiltration of leukocytes in the infected area (Sato M, Hosoya M, Honzumi K, Watanabe M, ninomiya N, Shigeta S, Suzuki H: Cytokine and cellular inflammatory response in enteroviral meningitis. Pediatrics 2003, 112(5):1103-1107).
The management of AMs caused by enterovirus is conducted with support therapies for symptom control since there is no drug licensed for clinical use that is effective against these pathogens. In contrast, BM treatment is conducted with antibiotics combined or not with anti-inflammatory drugs. Delays in the administration of antibiotics and anti-inflammatory drugs can have devastating consequences for the patient affected by BM (development of neurosensory sequelae and even death). In case of any suspicion of BM, empiric antibiotic therapy is initiated in order to obtain the results of CSF culture tests.
Thus, the fast differential diagnosis of AM and BM could reduce the hospitalization time of patients affected by AM, treatment costs, patients' exposure to the risk of nosocomial infections, and side effects of antibiotics and anti-inflammatories. Thus, accurate and rapid diagnosis of meningitis is crucial for decision making related to the appropriate therapeutic approach and should be timely for each form of meningitis.